Muscle and myotonic diseases

Muscle and myotonic diseases

Although the history and clinical examination remain the most effective way of diagnosing the presence of myopathy, increasingly the clinician has to rely on an understanding of muscle electrophysiology, pathology, and genetics to differentiate between an ever-increasing number of complex disorders of mus- cle.

The basis of the motor system is the motor unit. The motor unit consists of the anterior horn cell, axon, muscle membrane and muscle fiber, and is the final common pathway leading to activation of the muscle. The number of motor units in individual muscles varies depending on size from 10 in extraocular muscles to more than 1000 in lower limb muscles. Electromyography allows us to determine if the abnormality of the motor unit points to a disorder of the axon, muscle membrane, or muscle fiber and allows accurate diagnosis. Acti- vation of the motor unit results in firing of muscle fibers and leads to muscle contraction. Striated muscle is made up of interdigitating thick filaments com- prising myosin, and thin filaments comprising actin, and dividing the sarcomere into A and I bands (Fig. 1). Myosin is composed of light and heavy meromyosin and acts as an ATPase, hydrolyzing ATP. Actin filaments comprise actins,

Introduction

Electrophysiology

Fig. 1. Human Skeletal Muscle showing the gross and microscopic structure. The sacroplasmic

reticulum (SR) is an intracellular membrane system. The T tubules are invaginations of the sarcolem-

ma, and communicate with the extracellular space. Ultrastructurally several components of the

muscle can be identified. The sarcomere (SA) represents the space between the Z discs. The A band

comprises thick filaments of myosin, with an overlap of actin at the edges. The H band represents pure

myosin, with a thickening in the center called the M line. The I band on either side of the Z line,

comprises thin filaments. The Z disc helps to stabilize the actin filaments

troponins, and tropomyosin. ATPase hydrolysis in the presence of calcium ions activates the troponin-tropomyosin system and permits sliding of actin on myosin filaments as predicted by the “sliding filament theory”. The force generated by a muscle is critically depended on its length. The more cross bridges between the filaments, the larger the force generated. In order to induce contraction there is first an increase in calcium ions in the sarcoplasmic reticulum following depolarization of the muscle membrane. The degree of increase in calcium ions equates with increased muscle tension, and is maxi- mal at 10

to 10

M. Between contractions calcium is sequestered in the sarcoplasmic reticulum. Electrodiagnosis is useful in diagnosing the myopa- thies. Firstly, it helps distinguish between primarily myopathic compared to neurogenic disorders, secondly it allows the distribution of the myopathy to be determined, and finally it gives some information about severity and prognosis.

Although electromyography can distinguish broad types of myopathic disor- ders, it cannot diagnose the specific myopathy. This requires analysis of the muscle pathology often coupled with biochemical and genetic analysis. Fur- thermore, some myopathies show evidence of both myopathic as well as neurogenic types of motor units, for example the inflammatory myopathies and disorders of fatty acid metabolism.

The second critical diagnostic evaluation in myopathic disorders is the muscle biopsy. Regular histology may diagnose many of the disorders listed in the following sections, and can recognize distinct histological patterns such as those seen in dermatomyositis, or some infective or toxic myopathies. How- ever, increasingly we rely on specific immunohistochemical studies to make an accurate diagnosis. Thus, in the dystrophinopathies antibodies to certain mus- cle proteins allow us to determine the specific muscle disease, or in mitochon- drial myopathies and other metabolic diseases the pathogenic enzyme system can be determined. Increasingly, patients with a metabolic myopathy present with significant symptoms of myalgia or myoglobinuria and have normal or minimally abnormal basic muscle histology, yet biochemical tests reveal signif- icant enzyme abnormalities that would otherwise be missed. However, even the most astute muscle pathologist is dependent on accurate clinical informa- tion to decide which of the numerous biochemical studies are most appropri- ate. Pathological evaluation of muscle should be performed even where genet- ic analysis is available because it provides information about the severity of the disease, characterizes the presence or absence of a specific protein, and provides a clinical correlate for an available treatment. As discussed below, even the presence of a specific gene mutation may produce widely varying biochemical changes in muscle due to the presence of gene modifying effects.

Characterizing the molecular genetics of muscle has become increasingly important in understanding the pathogenesis of myopathy. Most gene defects have been described in the following chapters. The resulting clinical profile is dependent not only on the gene, but also on whether the disorder is autosomal recessive or dominant, the chromosomal localization, size of the gene defect, exon number, the type of gene promoter or enhancer, transcription characteris- tics, and the number and extent of deletions. A further important effect is that of compensatory or modifying alleles e.g. the utrophin gene can modify the

Muscle histology and immunohistochemistry

Regulation of gene

defects in muscle

severity of some dystrophinopathies. A mutation of the same gene can cause

widely differing clinical phenotypes. For example, the same mutation of the

dysferlin gene may cause either type 2B limb-girdle dystrophy or Miyoshi’s

distal myopathy. In the mitochondrial myopathies, or disorders of β-oxidation,

combinations of gene defects coding for specific enzymes can significantly

modify the clinical phenotype. Unfortunately, the exponential increase in

knowledge of genetic defects in specific muscle disorders has not been

matched by the diagnostic availability of these tests. Furthermore, the cost of

genetic studies has made it imperative that the clinician use consummate

diagnostic skills to define the type and extent of testing. Thus, clinical judge-

ment still remains the yardstick for diagnosis of a specific myopathy. As

effective treatments become aligned with specific genetic and post-translation-

al peptide or protein abnormalities, it will become even more important for the

physician to develop a superb diagnostic acumen.

Usually affects proximal muscles with sparing of the face.

Progressive disorder with gradual onset in most cases. Occasionally acute onset is described.

Average age is 35 years. Can occur in children, but usually in those greater than 20 years of age.

Polymyositis is more common in women (9:1). It usually results in a progres- sive, subacute weakness with muscle pain in approximately 50% of subjects.

There is usually proximal weakness of limb (Fig. 2A) and neck flexor muscles, dysphagia, and occasional weakness of respiratory muscles. Cardiac involve- ment with EKG changes may also occur.

There is targeted, cell mediated lymphocyte toxicity against muscle fibers. An increase in CD8-T lymphocytes and macrophages is seen in affected muscle fibers. Muscle fibers may be destroyed by cytotoxic T cells possibly by produc-

Polymyositis (PM)

Distribution/anatomy Time course

Onset/age

Clinical syndrome

Pathogenesis

Genetic testing NCV/EMG Laboratory Imaging Biopsy

– +++ + + +++

B A

Fig. 2. Polymyositis. A Clinical

proximal weakness on raising

the leg in a patient with severe

polymyositis. B Polymyositis

showing increased infiltration

of muscle fibers by macrophag-

es and rare lymphocytes (ar-

rows)

tion of the pore forming protein perforin, by upregulation of Fas-induced apoptosis, or by induction of oxidative intermediates such as nitric oxide and peroxynitrites due to upregulation of nitric oxide synthase. There is also upreg- ulation of anti-apoptotic molecules for example Bcl-2 on the surface of muscle fibers, implying that loss of muscle cells eventually occurs by necrosis and not apoptosis.

Laboratory:

An elevated CK, at least 5–10 times normal, AST, and LDH may be observed.

The following antibodies may be positive: Anti aminoacyl t-RNA synthetases e.g. JO1, and PM1.

Electrophysiology:

On EMG, there is increased insertional activity with short duration polyphasic motor unit action potentials. Nerve conductions studies are usually normal.

Imaging:

In early polymyositis, the muscle may be homogeneous on MRI. At sites of active inflammation there may be increased signal with gadolinium or on T2 weighted images. In chronic disease the muscle may be replaced by fat and show atrophy.

Muscle biopsy:

Evidence is found of focal areas of inflammation within perimysial connective tissue and surrounding blood vessels (Fig. 2B). There is usually scattered muscle fiber necrosis and an increase in CD8-T positive cells that traverse the basal lamina and focally compress and replace segments of muscle.

– Dermatomyositis – Inclusion Body Myositis – Muscular Dystrophies – Polymyalgia Rheumatica

– Prednisone: 1 mg/kg P.O. per day, up to a maximum of 100 mg/day.

– Intravenous immunoglobulin (IVIG): 1 g/kg I.V. monthly.

– Azathioprine: 2–3 mg/kg P.O. per day. Especially in adults over the age of 50 and those who are severely weak.

– Mycophenylate mofetil 500–2000 mg/day P.O. in divided doses.

– In resistant individuals: cyclophosphamide or methotrexate may be re- quired.

– General management includes dietary counseling, twice yearly eye evalua- tions for cataracts and glaucoma, supplemental calcitriol 0.5 mg/day, ele- mental calcium 1,000 mg/day, a regular graded exercise program, CK mon- itored at 2–4 weekly intervals coupled with strength testing and regular monitoring of serum electrolytes and glucose.

– Once the patient is stable or improved, the prednisone is tapered by approximately 10%, to an every other day dosage at 4 weekly intervals. The dose should be maintained at a steady state if the patient shows a decrease in strength or elevation of their CK level.

Diagnosis

Therapy

Differential diagnosis

Generally good with most patients showing response to therapy.

Ascanis V, Engel WK, Alvarez RB (1992) Immunocytochemical localization of ubiquitin in inclusion body myositis allows its light-microscopic distinction from polymyositis. Neurol- ogy 42: 460–461

Choy EH, Isenberg DA (2002) Treatment of dermatomyositis and polymyositis. Rheumatol- ogy (Oxford) 41: 7–13

Dalakas MC (1998) Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology 51:

S37–45

Engel AG, Hohlfeld R, Banker BQ (1994) The polymyositis and dermatomyositis syn- dromes. In: Engel AG, Franzini-Armstrong C (eds) Myology. McGraw Hill, New York, pp 1335–1383

Griggs RC, Mendell JR, Miller RG (1995) Evaluation and treatment of myopathies. FA Davis, Philadelphia, pp 154–210

Hilton-Jones D (2001) Inflammatory muscle diseases. Curr Opin Neurol 14: 591–596

Prognosis

References

Usually affects proximal muscles and bulbar muscles.

Progressive disorder with gradual onset in most cases.

Any age, bimodal frequency 5–15 years and 45–65 years.

Equally common in men and woman. Symptoms include myalgias, with sub- acute development of muscle weakness and dysphagia. Patients may also develop a rash (Fig. 3) with arthralgias, joint contractures and systemic symp- toms related to cardiac or pulmonary involvement. DERM is associated with proximal muscle weakness, including weakness of the neck flexors, dysphagia and ventilatory failure. This is associated with erythema and telangiectasis over

Dermatomyositis (DERM)

Distribution/anatomy Time course

Onset/age

Clinical syndrome

Genetic testing NCV/EMG Laboratory Imaging Biopsy

– +++ + + +++

Fig. 3. Patient with dermatomy- ositis. There is evidence of a hyperememic rash on the upper chest, face and palm

Fig. 4. Dermatomyositis. A Typ-

ical perifascicular regeneration

(arrows). B Necrotic capillaries

demonstrated by dark precipi-

tates on alkaline phosphatase

(arrow heads)

the face with a violet discoloration (heliotrope) around the eyes, papular erythematous changes may be present on the knuckles called Gottron’s pap- ules, dilated capillaries at the base of the fingernails (Keinig’s sign), nail fold capillary infarcts, dry and cracked skin on the palms (mechanic’s hands).

Necrotizing vasculitis may affect several organ systems including the retina, kidneys, gastrointestinal tract, heart and lungs.

In DERM there is myonecrosis with evidence of immunoglobulin and comple- ment deposition in the microvasculature, suggesting a systemic immune-medi- ated response. There is probably an increased risk of cancer in subjects within 3 years of diagnosis of DERM. DERM following treatment with interferon α2b has also been observed.

Laboratory:

Serum CK is elevated in more than 90% of patients with DERM. The following antibodies may be positive: Mi-2, MAS, sometimes Jo-1, anti t-RNA synthetase (anti-synthetase syndrome – myositis, polyarteritis, Raynauds, interstitial lung disease).

Electrophysiology:

Evidence of increased insertional activity with fibrillations and positive waves on EMG. Complex repetitive discharges may be seen with polyphasic motor units, many of which are short duration. With advanced disease the motor units may be frankly myopathic.

Imaging: May show evidence of inflammation and atrophy in chronically affected muscles.

Muscle biopsy:

Perifascicular muscle fiber atrophy (Fig. 4) is specific for DERM and occurs in 75% of patients. There may also be evidence of focal invasion of muscle fibers by inflammatory cells, although this is infrequent. There is a high proportion of CD4 positive T cells in DERM compared to PM or inclusion body myositis.

– Polymyositis

– Inclusion body myositis – Muscular dystrophies – Polymyalgia rheumatica

– Prednisone: 1 mg/kg P.O. per day, up to a maximum of 100 mg/day.

– IVIG: 1 g/kg I.V. monthly.

– Azathioprine: 2–3 mg/kg P.O. per day. Especially in adults over the age of 50 and those who are severely weak.

– Mycophenylate mofetil 500–2000 mg/day P.O. in divided doses.

– In resistant individuals: cyclophosphamide or methotrexate may be re- quired.

– General management as for PM.

Generally worse than with PM.

Pathogenesis

Diagnosis

Differential diagnosis

Therapy

Prognosis

Callen JP (2000) Dermatomyositis. Lancet 355: 53–57

Dalakas MC (2001) The molecular and cellular pathology of inflammatory muscle diseas- es. Curr Opin Pharmacol 1: 300–306

Engel AG, Hohlfeld R, Banker BQ (1994) The polymyositis and dermatomyositis syn- dromes. In: Engel AG, Franzini-Armstrong C (eds) Myology. McGraw Hill, New York, pp 1335–1383

Griggs RC, Mendell JR, Miller RG (1995) Evaluation and treatment of myopathies. FA Davis, Philadelphia, pp 154–210

References

Affects proximal and distal muscles in upper and lower extremities, with distal muscles affected predominantly in 20% of patients. Wrist and finger flexors and quadriceps are often more severely affected. Proximal arm, hand and face muscles are spared.

The disorder is progressive over 5 to 25 years More common in males over age 50 years.

Weakness and atrophy occurs in the distribution described above. Muscle weakness is often asymmetric unlike PM and DERM. Dysphagia is seen in 30%

of patients. Tendon reflexes are normal or decreased with disease progression.

A mild sensory neuropathy is observed in some patients. Systemic involvement is rare.

Unknown. No association with malignancy. An association with myxovirus has not been confirmed, inflammation is present but it is unknown if it is primary or secondary. The β-amyloid protein may result in muscle fiber apoptosis, and some cases are inherited (HaD).

Laboratory:

Mildly elevated CK, at least 2-5 times normal, but may be normal. The ESR is usually normal. There may also be an elevation in muscle AST and LDH up to

Inclusion body myositis (IBM)

Distribution/anatomy

Time course Onset/age

Genetic testing NCV/EMG Laboratory Imaging Biopsy

- +++ + +/- +++

Clinical syndrome

Pathogenesis

Diagnosis

Fig. 5. Inclusion Body Myositis.

A Hematoxilin and eosin

stained tissue showing a typical

rimmed vacuole in the center

(small arrow) and atrophy of

muscle fibers (large arrow). B

Acid phosphatase stain showing

rimmed vacuoles (arrows)

20 times normal. May be associated with various HLA types including DRb1*0301, DRb3*0101, DRb3*0202 and DQb1*0201. Genetic testing for inherited cases is not clinically available at this time.

Electrophysiology:

Nerve conductions studies are usually normal. EMG shows increased insertion- al activity. Short duration polyphasic motor unit action potentials, mixed with normal and long duration units are frequently observed. The presence of longer duration, polyphasic units may be misinterpreted as a neurogenic condition such as motor neuron disease.

Imaging:

Similar to dermatomyositis, but of limited clinical value.

Muscle biopsy:

Endomysial inflammation (mainly CD8+ T cells and some macrophages), with myopathic changes and groups of small fibers. Muscle fiber hypertrophy is more common than in polymyositis, and small groups of atrophic fibers of mixed histochemical type may be seen similar to that observed with denerva- tion of the muscle. Frequently rimmed vacuoles are seen with granular material and filaments measuring 15 to 18 nm (Fig. 5). These may comprise several proteins including b-amyloid, desmin, and ubiquitin.

– Polymyositis – Dermatomyositis – Motor Neuron Disease – Muscular dystrophies – Distal myopathies

No effective therapy. A high dose of IVIG is reported to be effective in some patients.

Survival is usually good, although weakness is progressive and may be debili- tating.

Askanas V, Engel WK (2001) Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 601–614

Askanas V, Engel WK (2002) Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol 15: 525–531

Askanas V, Engel WK, Alvarez RB, et al (1992) Beta-Amyloid protein immunoreactivity in muscle of patients with inclusion-body myositis. Lancet 339: 560–561

Dalakas MC (2002) Myosites a inclusions: mechanismes etiologiques. Rev Neurol 158:

948–958

Griggs RC, Mendell JR, Miller RG (1995) Evaluation and treatment of myopathies. FA Davis, Philadelphia, pp 154–210

Differential diagnosis

Therapy

Prognosis

References

May involve any muscle, although the quadriceps; gastrocnemius, and abdom- inal muscles are commonly affected.

May occur at any age from childhood to 70 years, mainly 30–50 years.

May occur at any age but is more common in subjects between 30 and 60 years of age.

There is an equal distribution in men and women. Symptoms include a painful, focal mass (Fig. 6) with muscle cramping. Patients may have a solitary, asym-

Focal myositis

Distribution/anatomy Time course

Onset/age

Clinical syndrome

Genetic testing NCV/EMG Laboratory Imaging Biopsy

- +++ + ++ +++

Fig. 7. Focal Myositis. A Atro- phic fibers (arrows top left), in- flammatory response (arrows bottom left), hypertrophied fiber (arrow head), increased con- nective tissue (top right). B Lob- ulated fibers outlined by bands of collagen (arrows)

Fig. 6. Calf hypertrophy. This

patient had a unilateral right calf

hypertrophy in a case of focal

myositis

metric muscle mass, enlarging over several months. Strength and reflexes are usually normal. Most cases spontaneously resolve, and recurrence is unusual.

Unknown. A focal inflammation develops in isolated muscles and may repre- sent a localized cell mediated response.

Laboratory:

Serum CK and ESR may be mildly elevated, but are usually normal.

Electrophysiology:

Nerve conduction studies are usually normal. EMG shows increased insertional activity only in affected muscles. Short duration polyphasic motor unit action potentials, mixed with normal and long duration units are seen in the affected muscle/s.

Imaging:

Focal enlargement and edema, especially observed on T2 weighted images and T1 with gadolinium.

Muscle biopsy:

Muscle fiber hypertrophy and fibrosis are more common than in PM and DERM. There is formation of clusters of tightly packed fibers surrounded by fibrosis (Fig. 7). Inflammation is mild, with predominant T-lymphocytes.

– Localized nodular myositis – Muscle sarcoma

– Sarcoid infiltration of muscle – Soft tissue tumors

– Analgesics and anti-inflammatory medications.

– Corticosteroids in a short course may help some patients.

Usually excellent and the swelling resolves spontaneously. Recurrence may occur in a minority of patients.

Caldwell CJ, Swash M, Van Der Walt JD, et al (1995) Focal myositis: a clinicopathological study. Neuromuscular Disorders 5: 317–321

Heffner R, Barron S (1981) Polymyositis beginning as a focal process. Arch Neurol 38:

439–442

Hohlfeld R, Engel AG, Goebels N, Behrens L (1997) Cellular immune mechanisms in inflammatory myopathies. Curr Opin Rheumatol 9: 520–526

Smith AG, Urbanits S, Blaivas M, et al (2000) The clinical and pathological features of focal myositis. Muscle & Nerve 23: 1569–1575

Pathogenesis

Diagnosis

Differential diagnosis

Prognosis

References

Therapy

Any muscle may be affected, although proximal muscles are more likely to be involved.

Variable, although involvement of muscle is unusual and tends to be seen more in chronic connective tissue disorders.

Can affect any age depending on the specific connective tissue disorder.

The following types of connective tissue diseases are associated with myopa- thy: 1) Mixed connective-tissue disease (MCTD); 2) Progressive systemic sclero- sis (PSS); 3) Systemic lupus erythematosus (SLE); 4) Rheumatoid arthritis (RA);

5) Sjögren’s syndrome (SS); 6) Polyarteritis nodosa (PAN); and 7) Behçet’s syndrome (BS).

– MCTD and PSS. Most patients develop a progressive weakness associated with fatigue. The weakness may be associated with an inflammatory myop- athy that resembles polymyositis, or may be associated with poor nutrition and disuse atrophy.

Connective tissue diseases

Distribution/anatomy

Time course

Genetic testing NCV/EMG Laboratory Imaging Biopsy

– +++ +++ + +++

Onset/age

Clinical syndrome

Fig. 8. Mixed connective tissue

disease. A prominent inflamma-

tory response is seen (arrow),

with a degenerating fiber (arrow

head)

– SLE. A true inflammatory myopathy is rare in this disorder. Other causes of weakness include a vasculitic neuropathy associated with mononeuritis multiplex or an axonal polyneuropathy. Myopathy in SLE may be related to inflammation, disuse atrophy secondary to painful arthritis, or following use of medications such as corticosteroids or chloroquin.

– RA. Causes of muscle weakness include disuse atrophy secondary to arthri- tis pain, inflammatory myopathy, and medications including penicillamine.

– SS. Myalgia is common in this disorder, but inflammatory myositis is rare.

Weakness is often due to disuse atrophy following joint pain.

– PAN. Although muscle biopsy may show evidence of vasculitis, symptomat- ic myopathy as a presenting disorder is rare in PAN.

– BS. Most patients present with painful calf or thigh symptoms, rather than muscle weakness. True myositis is unusual.

The immunopathogenesis of myositis with connective tissue disease is poorly understood. The presence of anti-RNP antibodies, circulating immune com- plexes, and reduced complement levels all suggest activation of the humoral immune system.

Laboratory:

The CK value is often very high up to 15 times normal, although CK values may only be mildly elevated in less severe cases.

Electrophysiology:

On EMG, there is evidence of an increase in insertional activity, coupled with short duration polyphasic motor unit action potentials observed in patients with connective tissue disease and inflammatory myopathy. Nerve conduction stud- ies may also show evidence of neuropathy in many of these disorders.

Imaging:

In MRI studies, there may be evidence of increased signal on T2 weighted images, or with gadolinium, indicating areas of active inflammation and mus- cle necrosis. In chronic disease there may be evidence of fat infiltration and muscle atrophy.

Muscle Biopsy:

Frequently the muscle biopsy shows changes that resemble those in DERM There may be necrotic fibers invaded by inflammatory cells (Fig. 8). Atrophy of type 2 muscle fibers may be observed particularly where there is significant arthritis, joint pain and disuse atrophy of the muscle.

– DERM – IBM – PM

– Causes of weakness associated with connective tissue disease e.g. poly- neuropathy or mononeuritis multiplex.

This is dependent on the specific cause of the connective tissue disease. In general immunosuppressive medication similar to that used for PM is appropri-

Pathogenesis

Diagnosis

Therapy

Differential diagnosis

ate for the treatment of inflammatory myopathy associated with connective tissue disease.

Depends mainly on the severity of the systemic illness. With appropriate control of the disease, the myopathy may become quiescent.

De Bleecker JL, Meire VI, Van Walleghem IE, et al (2001) Immunolocalization of FAS and FAS ligand in inflammatory myopathies. Acta Neuropathol (Berl) 101 (6): 572–578 de Palma L, Chillemi C, Albanelli S, et al (2000) Muscle involvement in rheumatoid arthritis: an ultrastructural study. Ultrastruct Pathol 24: 151–156

Isenberg D (1984) Myositis in other connective tissue disorders. Clin Rheum Dis 10: 151–

174

Hengstman GJ, Brouwer R, Egberts WT, et al (2002) Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies. J Neurol 249: 69–75

Mastaglia FL (2000) Treatment of autoimmune inflammatory myopathies. Curr Opin Neurol 3: 507–509

Prognosis

References

Infections of muscle

Genetic testing NCV/EMG Laboratory Imaging Biopsy

– ++ +++ + +++

Fig. 9. HIV myopathy. Proximal arm atrophy and bilateral scap- ular winging in a patient with HIV myopathy

Fig. 10. Pyomyositis. A Marked

neutrophil inflammation (ar-

row). The muscle fibers are tex-

tureless and have no nuclei,

features consistent with rhab-

domyolysis. B Neutrophil in-

flammatory response dispersed

between several fibers

The distribution is variable depending on the type of infection.

Is variable depending on the type of infection.

Any age.

Influenza virus myositis is characterized by severe pain, tenderness and swell- ing which usually affects the calf muscles but may also affect thigh muscles.

Myalgia is the most common symptom, and starts approximately one week after the onset of the influenza infection, and then persists for another 2–3 weeks.

The disorder is usually self-limiting, however in rare cases it may be severe with myoglobinuria and a risk of renal failure. Coxsackie virus infection is character- ized by a wide spread acute myositis which may be severe and may be associated with myoglobinuria. Epidemics of Coxsackie virus infection tend to occur during the summer and fall. In children aged 5–15 years there may be a self-limiting acute inflammatory myopathy. Infection is usually caused by Coxsackie virus group B. Affected patients may complain of muscle aching, often exacerbated by exercise, and weakness if it occurs may be minimal. The symptoms usually resolve within 1–2 weeks. Bornholm’s disease is associated with severe pain and tenderness in the muscles of the chest, back, shoulders, or abdomen and may be associated with a more severe Coxsackie B5 infection.

The human immunodeficiency virus (HIV), and human T-cell lymphotrophic virus (HTLV) may be associated with a variety of myopathic manifestations. HIV infected patients may develop one of the following manifestations: a) An HIV associated myopathy (Fig. 9) that resembles polymyositis. b) Zidovudine myop- athy, which resembles mitochondrial myopathy. c) AIDS-associated cachexia with muscle wasting. d) Opportunistic infections and tumor formation within muscle. e) A myopathy resembling nemaline myopathy. f) An HIV associated vasculitis. With HIV associated nemaline rods, the CK is often very high and

Distribution/anatomy Time course

Onset/age

Clinical syndrome Viral myositis

Fig. 11. Trichinella spiralis.

Slide shows a calcified cyst

within the muscle (arrow)

there may be evidence of muscle fiber necrosis. HIV may also be associated with a necrotizing myopathy with proximal weakness. Pyomyositis and lym- phoma may also develop in the muscle, and may be associated with painful limb swelling. A variety of organisms have been associated with pyomyositis including cryptococcus, CMV, Mycobacterium avium intracellularae (MAI), and toxoplasma. With HIV wasting disease, which is more common in sub Saharan Africa, there is fatigue and evidence of type 2 muscle fiber atrophy.

HTLV1 may also be associated with polymyositis, as well as causing a tropical spastic paraparesis (TSP).

Pyomyositis associated with staphylococcus, streptococcal and clostridial in- fections are the most common forms of bacterial myositis. Pyomyositis most commonly occurs in tropical areas and may occur without any antecedent illness or other predisposing factors. It may also be associated with trauma, malnutrition, diabetes mellitus, following an acute viral infection, associated with a suppurative arthritis or osteomyelitis, or from hematogenous spread from a bacterial source within the body. Non-tropical pyomysitis may occur in elderly bed ridden patients with bed sores, intravenous drug users, burn vic- tims, in immunosuppressed patients, e.g. AIDS or underlying cancer. In the vast majority of cases, Staphylococcus aureus is cultured from the abscesses, how- ever other organisms including Streptococcus pyogenes, salmonella, and pneu- mococcus may also be isolated from the abscess. Clinically there is painful swelling of the muscle, the pyomyositis often affects the quadriceps, glutei muscles, biceps or pectoral muscles. Although the swelling may initially be hard, it rapidly becomes fluctuant as the inflammation increases and muscle necrosis occurs. Clostridial myositis is due to infection with Clostridium welchii, and develops after wound or muscle contamination. The clinical features of clostridial myositis include local pain, swelling, production of serosanguinous fluid, and local brownish discoloration. Patients may develop systemic signs of septicemia. Necrotizing fasciitis and myonecrosis (a flesh eating infection) is a rare but life-threatening disease, most often caused by group A β-hemolytic Streptococcus pyogenes. The disorder may occur post- operatively, or following minor trauma. There is destruction of skin and muscle in response to streptococcal pyrogenic exotoxin A.

Fungal myositis is uncommon in man. In immunocompromised patients, fungal myositis is becoming increasingly more common in those suffering from AIDS or with malignancies. Sporotricosis, histoplasmosis, mucormycosis, candidia- sis, and cryptococcosis are all associated with myositis. In sporotricosis and histoplasmosis a single muscle or group of muscles is usually affected with formation of an abscess. Mucormycosis can spread into the orbit where it produces ophthalmoplegia, proptosis, and edema of the eyelid. In disseminated candidiasis, patients develop papular cutaneous rashes, and wide spread mus- cle weakness with myalgia. Toxoplasmosis may cause local inflammation within the muscle. In immunocompromised hosts it is often asymptomatic, however in other infected subjects, an acute infection may develop with lymphadenopathy which may remit spontaneously, and in some patients a polymyositis-like syndrome may develop.

American trypanosomiasis (Chagas’ disease) caused by Trypanosoma cruzi can cause an inflammatory myopathy coupled with evidence of a neuropathy. In

Pyomyositis

Fungal myositis

Parasitic myositis

African trypanosomiasis, there is malaise and fever along with myocarditis, polymyositis and encephalopathy. Microsporidiosis is caused by the zoonotic protozoa, microsporidium, and results in polymyositis in immunocompromised patients. In addition to causing the systemic illness malaria, plasmodium falciparum can also cause acute muscle fiber necrosis. Cysticercosis results from infection by Cysticercus cellulosae, the larval form of the pork tapeworm Taenia solium. The encysted parasite may be found in skeletal and heart muscle, as well as eye and brain. The clinical features vary according to the location and number of cysts, however myalgia, fever, and vomiting may occur as part of the overall syndrome. Trichinosis is caused by the larva of Trichinella spiralis and may be associated with periorbital and facial edema, fever, myal- gia, and proximal muscle weakness. Occasionally the disorder may mimic mild dermatomyositis. Myositis is also reported with echinococcosis, visceral larva migrans, cutaneous larva migrans, coenurasis, sparganosis and dracunculosis.

The specific mode of muscle injury depends on the particular pathogen. Several of the viral infections, including HIV may cause myositis by increasing release of cytokines and interferons. Viral infections may also cause perivascular, perimysial, or endomysial inflammation. In streptococcous pyogenes infections the pathogenic M-protein and associated proteases may prevent the normal host phagocytic response.

Laboratory:

The CK value may be normal or mildly elevated.

Electrophysiology:

EMG shows evidence of focal or more diffuse muscle damage, characterized by increased insertional activity or with “myopathic” polyphasic motor unit poten- tials.

Imaging:

MRI studies may show evidence of a focal myositis depending on the specific pathogen.

Muscle biopsy:

The muscle biopsy changes depend on the specific pathogen. In general the features are similar to those observed in polymyositis (Fig. 10). In certain disorders such as HIV, nemaline rods may be observed. In the parasitic infec- tions, the specific parasite may be observed, e.g. cysticercosis, trichinosis (Fig. 11), echinococcosis, and trypanosomiasis. Likewise, with the fungal infec- tions, the specific pathogen may be identified in the muscle tissue.

Many of the causes of infectious myositis resemble one another, and determin- ing the specific cause may require culture of the organism, specific antibody testing and muscle biopsy with special staining. Other disorders that may resemble infectious myopathy include: 1. Polymyositis 2. Dermatomyositis 3. Mitochondrial myopathies 4. Necrotizing myopathy

Therapy for the specific infectious myositis depends on the specific pathogen, and is beyond the scope of this book. In addition to use of specific anti-infective

Pathogenesis

Diagnosis

Differential diagnosis

Therapy

drugs, patients may require surgical drainage of the abscess, or removal of the parasite. HIV polymyositis is similar to disease in non-HIV patients and may improve with corticosteroids or immunosuppressive medications. Some pa- tients with the HIV wasting disorder, may respond to oxandrolone.

The prognosis depends on the specific cause of the myositis. For a non-HIV related viral syndrome, the disease is usually self-limiting and prognosis is good. Where there is HIV infection or opportunistic infection the prognosis is poor. Removal of isolated parasites coupled with anti-protozoal medications may be all that is required to treat parasitic myositis.

Banker BQ (1994) Parasitic myositis in myology. In: Engel AJ, Franzini-Armstrong C (eds), McGraw Hill, New York, pp 1453–1455

Chimelli L, Silva BE (2001) Viral myositis in structural and molecular basis of skeletal muscle diseases. In: Karpati G (ed), ISN Neuropathology Press, Basel, pp 231–235 Dalakas MC (1994) Retrovirus-related muscle diseases in myology. In: Engel AJ, Franzini- Armstrong C (eds), McGraw Hill, New York, pp 1419–1437

Prognosis

References

Proximal muscles are more affected than distal muscles. Infants may have generalized hypotonia and be described as “floppy”.

Progressive disorder resulting in significant disability in most children.

DMD starts at age 3–5 years with symmetric proximal greater than distal weakness in the arms and legs. By 6–9 years they characteristically exhibit a positive Gower’s sign, and by 10–12 years patients often fail to walk.

DMD results in a progressive muscular weakness affecting 1:3500 male infants.

They often have calf muscle hypertrophy, muscle fibrosis, contractures in the lower extremities, and scoliosis of the spine. In general the average IQ of affected children is reduced compared to the general population to approxi- mately 85. Some patients (20%) may have more severe cognitive impairment.

Other features include a retinal abnormality with night blindness, and a cardio- myopathy that develops by the mid-teens. In DMD, cardiac conduction de- fects, resting tachycardia, and cardiomyopathy are frequently encountered.

Mitral valve prolapse and pulmonary hypertension may also be seen. Death normally occurs by the late teens to early twenties from respiratory or cardiac failure.

Genetic testing NCV/EMG Laboratory Imaging Biopsy

+++ ++ – + +++

Duchenne muscular dystrophy (DMD)

Distribution

Time course Onset/age

Clinical syndrome

Fig. 12. Muscle biopsy DMD. A

Hematoxylin and eosin show-

ing an increase in endomysial

connective tissue (large arrows),

inflammatory infiltrates (small

arrows), and degenerating fibers

(arrow head). B Normal dystro-

phin staining. C Loss of dystro-

phin staining in DMD

Most have a frameshift mutation (> 95%), although 30% may have a new mutation. The molecular abnormality is unknown. However, in DMD there is an abnormality in dystrophoglycan development at the neuromuscular junc- tion. Dystrophoglycan may play a role in clustering of acetylcholine receptors and development of the neuromuscular junction, along with dystroglycan, α1- syntrophin, utrophin, and α-dystrobrevin.

Laboratory:

Serum CK is usually very high.

Electrophysiology:

Nerve conduction studies are usually normal (except reduced CMAP in affected atrophic muscles). EMG shows increased insertional activity only in affected muscles. Short duration polyphasic motor unit action potentials, mixed with normal and long duration units are seen in the affected muscle/s.

Imaging: Focal enlargement, edema, and fatty infiltration especially observed on T2 weighted and T1 images with gadolinium. Imaging may show hyperlor- dosis and scoliosis.

Muscle biopsy:

Characterized by endomysial fibrosis (Fig. 12), variation in muscle fiber size, muscle fiber degeneration and regeneration, small fibers are rounded, there are hypercontracted muscle fibers, and an increase in endomysial connective tissue. Muscle dystrophin staining is absent (Fig. 12C).

Genetic testing:

Exonic or multiexonic deletions (60–65%), duplication (5–10%), or missense mutations that generate stop codons may be found. Genetic testing is helpful in most affected cases.

– Becker’s muscular dystrophy – Congenital myopathies – Inflammatory myopathies

– Spinal muscular atrophies (SMA).

– Prednisone therapy may prolong the ability to walk by a few years, and reduce falling. The doses are usually 0.75 mg/kg/day as a starting dose and then changing to a weekly dose of 5 to 10 mg/kg, or Oxandrolone 0.1 mg/

kg/day.

– Non-surgical treatment of contractures consists of night splints and daytime passive stretch.

– Surgical treatment of contractures consists of early contracture release, Achilles tenotomy, posterior tibial tendon transfer followed by early ambu- lation.

– Scoliosis – back bracing. Spinal fusion may be required where there is respiratory compromise: according to Hart and McDonald, fusion should be used before the curvature is greater than 30

and vital capacity is less than 35% of predicted.

Pathogenesis

Diagnosis

Differential diagnosis

Therapy

– Patients with cardiomyopathy and pulmonary hypertension may be helped by angiotensin converting enzyme inhibitors and supplemental oxygen.

Digoxin may be used in selected patients. Carriers should also be checked for cardiac defects.

– Respiratory compromise may require portable positive pressure ventilation.

– Prophylactic antibiotics should be used for dental and surgical procedures in patients with mitral valve prolapse.

– In the future, adeno-associated viruses show the greatest promise of transfer of normal DNA to affected muscles. Myoblast, DNA, and stem cell transfer are potential therapies.

Patients usually survive to their mid-twenties.

Cohn RD, Campell KP (2000) Molecular basis of muscular dystrophies. Muscle Nerve 23:

1456–1471

Fenichel GM, Griggs RC, Kissel J, et al (2001) A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy. Neurology 56: 1075–1079 Grady RM, Zhou H, Cunningham JM, et al (2000) Maturation and maintenance of the neuromuscular synapse: genetic evidence of for the roles of the dystrophin-glycoprotein complex. Neuron 25: 279–293

Hart DA, McDonald CM (1998) Spinal deformity in progressive neuromuscular disease.

Phys Med Rehab Clin N America 9: 213–232

Jacobsen C, Cote PD, Rossi SG, et al (2001) The dystrophoglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol 152: 435–450

Mirabella M, Servidei S, Manfredi G, et al (1993) Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy. Neurology 43: 2342–

2345

Prognosis

References

BMD affects proximal greater than distal muscles. Worse in the quadriceps and hamstrings.

BMD is a progressive disorder with a slower rate of progression than DMD.

BMD is much milder than DMD with later clinical onset. Patients may have difficulty walking by their late teens.

BMD often causes calf pain, cramps, and myalgias. Weakness is present in approximately 20% of affected patients. Patients may have no symptoms. In general the severity and onset age correlate with muscle dystrophin levels. As with DMD, affected subjects may have calf muscle hypertrophy and contrac- tures in the lower extremities. Patients with BMD often have a severe cardio- myopathy as part of the muscle weakness syndrome, or may have an isolated dilated cardiomyopathy. In general the average IQ of affected children is re- duced compared to the general population and may be a major presenting symptom in BMD. Some patients may present with an atypical neuromuscular disorder mimicking SMA, a focal myopathy, or a limb girdle muscular dystrophy.

Most are exonic or multiexonic (70–80%), although duplications can occur in 10%, and missense mutations in < 10%. Although dystrophoglycan is reduced in BMD, the molecular abnormality is unknown although it is likely similar to DMD. In some affected subjects there is a deficiency of mitochondrial enzymes and downregulation of several mitochondrial genes.

Laboratory:

Serum CK is high in 30% of subjects.

Electrophysiology:

Nerve conduction studies are usually normal. If the EMG is abnormal it shows increased insertional activity only in affected muscles. Short duration polypha- sic motor unit action potentials, mixed with normal and long duration units are seen in the affected muscles.

Imaging:

Focal enlargement, edema and fatty tissue replacement is observed on T2 and T1 weighted images with gadolinium in more severely affected patients.

Becker muscular dystrophy (BMD)

Distribution

Genetic testing NCV/EMG Laboratory Imaging Biopsy

+++ ++ – + +++

Onset/age

Clinical syndrome

Pathogenesis Time course

Diagnosis

Muscle biopsy:

There may be variation in muscle fiber size, an increase in endomysial connec- tive tissue, increased myopathic grouping, and evidence of degeneration and regeneration of muscle fibers. There is also evidence of reduced dystrophin staining.

Genetic testing:

Exonic or multiexonic deletions (60–65%), duplication (5–10%), or missense mutations that generate stop codons may be observed. Genetic testing is helpful in most affected cases.

– Congenital myopathies – SMA

– Limb girdle dystrophy – Focal myopathies.

– Prednisone therapy may help in more severely affected subjects.

– Treatment of contractures, cardiac, and pulmonary disease follows the outlines for DMD.

– Many subjects have mild symptoms and do not require therapy.

Koenig M, Hoffman EP, Bertelson CJ, et al (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50: 509–517

Mostacciuolo ML, Miorin M, Pegoraro E, et al (1993) Reappraisal of the incidence rate of Duchenne and Becker muscular dystrophies on the basis of molecular diagnosis. Neuro- epidemiology 12: 326–330

Nigro G, Comi LI, Politano L, et al (1995) Evaluation of the cardiomyopathy in Becker muscular dystrophy. Muscle Nerve 18: 283–291

Piccolo G, Azan G, Tonin P, et al (1994) Dilated cardiomyopathy requiring cardiac transplantation as initial manifestation of XP21 Becker type muscular dystrophy. Neuro- muscul Disord 4: 143–146

Vita G, Di Leo R, De Gregorio C, et al (2001) Cardiovascular autonomic control in Becker muscular dystrophy. J Neurol Sci 186: 45–49

Differential diagnosis

Therapy

References

DM affects both distal and proximal muscles, as well as many other organ systems.

Slowly progressive disorder.

Variable age of onset.

DM affects approximately 1:7400 live births, although it is much rarer in sub- Saharan regions, suggesting that the mutation developed post-migration from Africa. DM1 affects many organ systems. There is considerable phenotypic variation within families. Both proximal and distal muscles are usually affected, and weakness usually follows years of myotonia. Facial muscle weakness with prominent mouth puckering, weak eye closure, and external ocular muscle weakness is common. Usually, symptomatic weakness begins in the hands and at the ankles, with hand strength and progressive foot-drop. Myotonia may be demonstrated in the thenar eminence, or tongue. Frequently affected organs

Myotonic dystrophy (DM)

Genetic testing NCV/EMG Laboratory Imaging Biopsy

+++ +++ + – ++

Onset/age

Clinical syndrome Distribution/anatomy

Time course

Fig. 13. Myotonic dystrophy.

The muscle biopsy shows atro-

phied fibers (small arrows),

mixed with hypertrophied fi-

bers (arrow head), and a slight

increase in endomysial connec-

tive tissue (large arrow)

include skeletal muscle, the cardiac conduction system, brain, smooth muscle, and lens. Sinus bradycardia is common, although heart block, and cardiac arrhythmias can be present. Dilated cardiomyopathy is unusual.

Cerebral signs and symptoms may be prominent in later years. In addition to cognitive impairment, patients may have a severe personality disorder. Later in the course of the disease, hypersomnolence may become apparent. Cataracts are common in typical DM, but are less common in epidemiological studies where genetic testing is used. Another frequent problem is insulin insensitivity.

Blood sugar levels are elevated and there is persistent hyperinsulinemia.

Where the expansion is small (< 100 CTG repeats), the phenotype is often very mild with cararacts as the sole manifestation, and muscle symptoms not appearing until the sixth decade.

In DM2 (proximal myotonic myopathy or PROMM) symptoms are often milder than DM1 and include proximal > distal weakness, myotonia, and white matter hyperintensity on the brain MRI.

DM1 is an autosomal dominant disease due to variable triplet repeat (CTG) mutation on chromosome 19. This region codes for myotonin protein kinase (DMPK gene). In patients with DM the mutation varies from 50 to several thousand repeats. Abnormalities in DMPK only partially explain the clinical abnormalities seen in DM. DMPK localizes to the motor endplate where it may regulate calcium homeostasis. In DMPK knockout mice there is a 40% reduc- tion in muscle force generation. Other genes affected in DM1 are SIX5 and DMWD. Reduced levels of SIX5 are associated with cataracts in mice. The role of DMWD in DM1 is unknown. Unlike DM1, DM2 is related to an expansion of the CCTG repeat in intron 1 of the ZNF9 gene. DM shows evidence of anticipation. The repeat usually becomes larger in subsequent generations, although exceptions to this rule occur.

Laboratory:

Serum CK is often normal.

Electrophysiology:

Nerve conduction studies are usually normal. If the EMG is abnormal it shows a minimal increase in insertional activity in affected muscles. There is often evidence of myotonic discharges especially in distal muscles. The myotonic discharges may be increased by cooling the muscle.

Muscle biopsy:

The muscle biopsy in both DM1 and DM2 is similar and shows type 1 fiber atrophy, central nuclei, atrophied fibers mixed with hypertrophied fibers, and a slight increase in endomysial connective tissue (Fig. 13). Ringbinden, charac- terized by peripheral myofilaments wrapped perpendicularly around the center of a fiber may be seen but are not pathognomonic of DM. Electron microscopy shows sarcoplasmic masses and dilation of the terminal cisternae of the sarco- plasmic reticulum.

Genetic testing:

Genetic evaluation has supplanted other tests in the diagnosis of DM. DNA testing using PCR or Southern blotting is available to measure the size of the unstable CTG repeat in blood or tissue DNA. Each test should be interpreted

Pathogenesis

Diagnosis

with care: a small myotonic dystrophy repeat may be missed by Southern blotting techniques, while a larger repeat may be missed by PCR methods.

Diagnostic (prenatal) tests include: 1) amniocentesis – this may not accurately represent CTG repeats in fetal blood 2) measuring CTG triplet repeats in mother and fetus.

The clinical manifestions of DM are very variable, and thus the disorder may remain undiagnosed when a family history is not available. This is especially true when cardiac arrhythmia or hypomotility of the bowel is the presenting complaint and where there is no overt muscle weakness or myotonia. Other conditions to be considered are:

– Myotonia congenita

– Cold induced myotonia (paramyotonia)

There is no specific therapy for DM. However the following are useful in management of these associated disorders:

– Monitor the EKG for cardiac disease. Gradual widening of the PR interval to greater than 0.22 msec provides a warning for impending heart block, and invasive electrophysiological testing for elective pacemaker placement should be considered.

– Hypersomnolence may occur later in life and may make employment difficult. Medication that may improve the somnolence are methylpheni- date, caffeine, and imipramine.

– Cognitive impairment and personality disorders require a combined ap- proach with medication and psychological support.

– The following medications may worsen the patient’s symptoms: amitrip- tyline, digoxin, procainamide, propranolol, quinine, and sedatives.

– Where there are at least 300 repeats in the villous sample and 600 repeats in mother, or where there is polyhydramnnios, the pregnancy should be treated as high risk with appropriate monitoring and if necessary early induction with or without a caesarian section.

DM shows variable progression, even in members of the same family. Earlier onset usually implies a rapid and severe disorder. Although survival to the fifth decade is common, survival beyond 65 years is rare. Late in the course of the disease, hypersomnolence becomes more problematic. The most frequent causes of death are pneumonia and cardiac arrhythmias.

Abbruzzese C, Krahe R, Liguori M, et al (1996) Myotonic dystrophy phenotype without expansion of (CTG)n repeat: an entity distinct from proximal myotonic myopathy (PROMM)? J Neurol 243: 715–721

Brook JD, McCurrach ME, Harley HG, et al (1992) Molecular basis of myotonic dystrophy:

expansion of a trinucleotide (CTG) repeat at the 3 end of a transcript encoding a protein kinase family member. Cell 68: 799–808

Lieberman AP, Fischbeck KH (2000) Triple repeat expansion in neuromuscular disease.

Muscle and Nerve 23: 843–846

Liquori CL, Ricker K, Moseley ML, et al (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293: 864–867

Phillips MF, Steer HM, Soldan JR, et al (1999) Daytime somnolence in myotonic dystrophy.

J Neurol 246: 275–282

Differential diagnosis

Therapy

Prognosis

References

In approximately 50% of subjects with LGMD, weakness begins in the pelvic girdle musculature (the Leyden and Möbius type), then spreads to the pectoral musculature, and in 50% (the Erb type) starts first with the pectoral girdle musculature.

Generally most causes of LGMD are slowly progressive.

Age of onset is variable depending on the specific cause of the LGMD. The autosomal recessive forms are more severe and start early in life, whereas the autosomal dominant forms are milder and start later. The weakness is progres- sive, and eventually all muscles in the body are affected.

LGMD is a very heterogenous disorder, where the clinical presentation depends on the gene defect. It occurs approximately equally in both sexes. There is a characteristic clinical appearance: drooped shoulders, scapular winging, and

“Popeye” arms (due to wasted arm muscles and spared deltoids). In the pelvic form of LGMD, sacrospinals, quadriceps, hamstrings, and hip muscles are especially involved, causing excessive lumbar lordosis and waddling gait.

Facial muscles are uninvolved in LGMD until the patient is severely disabled from limb weakness. Pseudo-hypertrophy of calf muscles is unusual. Muscle tendon reflexes are preserved in the early stages, but are lost as the disease progresses. As the disease progresses, there may be respiratory failure associat- ed with axial weakness and scoliosis.

Limb girdle muscular dystrophy

Distribution

Genetic testing NCV/EMG Laboratory Imaging Biopsy

++ ++ + – ++

Time course Onset/age

Clinical syndrome

Fig. 14. Limb girdle dystrophy.

There is an increase in connec-

tive tissue (large arrow), the

presence of nesting muscle fi-

bers (arrow heads), muscle atro-

phy (small arrow), and a hyper-

trophied fiber (small arrow

head)

Understanding the specific genetic mutations in this heterogeneous condi- tion is helpful in separating out the individual pathogenetic and clinical disor- ders. Specific types are characterized below:

Autosomal dominant:

1A: Myotilin; 5q31 1B: Lamin A/C; 1q21 1C: Caveolin-3; 3p25 1D: 7q

Bethlem myopathy: Collagen VI Autosomal recessive:

2A: Calpain-3; 15q15 2B: Dysferlin; 2p12

2C: gamma-sarcoglycan; 13q12 2D: alpha-sarcoglycan; 17q21 2E: beta-sarcoglycan; 4q12 2F: delta-sarcoglycan; 5q33 2G: Telethonin; 17q11–12 2H: TRIM32; 9q31–q33 2I: FKRP; 19q13.3

– Chromosome 1q21-linked LGMD (Lamin A/C deficiency): Proximal weak- ness with cardiac involvement.

– Chromosome 2p12 (Dysferlin) – linked LGMD: Weakness of the pelvic girdle musculature is common, and resembles chromosome 15q LGMD. In rare cases distal muscles are affected, but cardiac and respiratory muscles are spared.

– Chromosome 3p25-linked LGMD (Rippling muscle disease – caveolin-3):

This autosomal dominant transmitted disorder likely results from single amino acid mutations of caveolin-3. Patient present early in childhood with a progressive aproximal muscle weakness, calf hypertrophy, cramping mus- cle pains, and a peculiar muscle rippling phenomenon.

– Chromosome 4q12-linked LGMD (beta-sarcoglycan): This autosomal reces- sive form of LGMD has been described in Amish families. The clinical features resemble those of calpain3-associated LGMD.

– Chromosome 5q31-linked LGMD (myotilin): This is an autosomal dominant form of LGMD, with age of onset ranging from 18–35 years. Characteristic clinical features include pelvic and pectoral girdle muscle involvement, weakness of neck flexor and facial muscles, dysarthria, tight heel cords, absent ankle jerks, and loss of ambulation at 40–50 years.

– Chromosome 5q33-linked LGMD (delta-Sarcoglycan): This is autosomal recessive.

– Chromosome 6q2-linked LGMD (laminin α2/merosin): This autosomal re-

cessive disorder presents with a clinical picture ranging from a severely

hypotonic infant where laminin α2 is completely absent to less severe forms

of LDMD with partial deficiency. Cognition is normal, but there is evidence

of severe white matter changes on the MRI. A demyelinating neuropathy

may be present, but is difficult to distinguish clinically from the severe

myopathy.

– Chromosome 13q12 LGMD (gamma-sarcoglycan): This autosomal reces- sive LGMD starts between 3–12 years and is characterized by pelvic weak- ness, inability to walk by 20–30 years, calf hypertrophy and cardiac involve- ment.

– Chromosome 15q15-linked LGMD (Calpain3): There is considerable varia- tion in the severity of this disease initially described among Amish families and families from La Reunion. Onset is usually before age 10 years, with a wide range of time before loss of ambulation and death. Shoulder and pelvic girdle muscles are affected, facial muscles are spared, calf muscle hypertro- phy is common, and the degree of clinical heterogeneity makes it difficult to distinguish from other forms of LGMD.

– Chromosome 17q11-12-linked LGMD (telethonin deficiency): This autoso- mal recessive LGMD starts ages 2–15 years and results in difficulty in the patient walking on their heels, proximal weakness of the arms and distal and proximal weakness of the legs. Facial and extraocular muscles are spared.

There may be cardiac involvement and muscle hypertophy.

– Chromosome 17q21-linked LGMD (α-sarcoglycan, primary adhalinopa- thy): In this autosomal recessive form of LGMD, the dystrophin-associated glycoprotein adhalin is absent in muscle fibers. Adhalin is primarily ex- pressed in skeletal muscle, but may also be found in heart muscle. The clinical severity of myopathy in patients with adhalin mutations varies considerably, and is most severe in patients homozygous for null mutations, who lack skeletal muscle adhalin expression. Missense mutations cause relatively milder phenotypes and variable residual adhalin expression. The clinical picture is very similar to other forms of LGMD. In addition, clinically indistinguishable secondary adhalin deficiency and LGMD may be associat- ed with loss of γ-sarcoglycan, coding to chromosome 13q12.

– Chromosome 21q-linked LGMD (Bethlem myopathy – collagen V1 gene mutation): This autosomal dominant LGMD begins in infancy. It is associat- ed with flexion contractures of the ankles, elbows and fingers, and affects both sexes equally. The progression is very slow, and most patients remain ambulatory until late in life.

– ITGA linked LGMD (α7 integrin deficiency): This is a severe form of LGMD with onset in infancy and associated with torticollis.

LGMD is a heterogenous disorder with a wide range of molecular defects.

LGMD1A is associated with a a missense mutation of the myotilin gene on chromosome 5q. It is not clear why these patients develop LGMD, since it is difficult to demonstrate a reduction, or accumulation of myotilin. LGMD1B is due primarily to missense mutations of the gene for lamin A and C which play a critical role in the structure of the nuclear membrane and are involved in DNA replication, chromatin organization, regulation of the nuclear pore, and growth of the nucleus. LGMD1C is likely due to a dominant negative effect since transgenic mice expressing the P104L mutant caveolin protein develop LGMD whereas knockout animals do not. Caveolin-3 is part of caveolae membranes and is likely critical in controlling lipid and protein interaction in the caveolae membrane, and possible controlling T-tubule organization. Al- though collagen VI is ubiqitously expressed in the body, for unknown reasons only skeletal muscle and tendon are affected in patients with Bethlem myopa-

Pathogenesis

thy. LGMD2B substitutions or deletions of the dysferlin gene (DYSF) results in non-specific myopathic changes in skeletal muscle. The phenotypical variation suggests that additional factors to mutations in the DYSF gene account for the defect. LGMD2C-2F constitute the sarcoglycanopathies. Loss of sarcoglycan results in structural weakness of the muscle cytoskeleton resulting in a clinical picture similar to Becker’s muscular dystrophy. The pathological mechanisms are complex but likely involve several mechanisms including impaired mito- chondrial function with energy depletion, loss of calcium homeostasis, necrosis of affected fibers, and loss of fiber regeneration. LGMD2G is due to a mutation of the gene coding for telethonin found in the myofibrillar Z-discs. It likely plays a role in control of sarcomere assembly and disassembly.

Laboratory:

Serum CK is usually elevated especially in the autosomal recessive forms of LGMD.

Electrophysiology:

Nerve conduction studies are usually normal. The principal findings on needle EMG are short duration, low-amplitude motor unit potentials, increased polyphasic potentials, and early recruitment. Increased insertional activity is seen in more rapidly progressive autosomal recessive LGMD. Progressive muscle fibrosis may also result in decreased insertional activity.

Muscle biopsy:

The muscle biopsy is nonspecific and depends on the particular type of LGMD.

In general there are a wide range of degenerative changes include fiber splitting, ring-fibers, and lobulated fibers. Individual muscle fibers showing hyalinization, vacuolation, and necrosis. Other changes include an increase in connective tissue with nesting of muscle fibers, and muscle atrophy (Fig. 14).

Regenerating fibers with prominent nucleoli and basophilic sarcoplasm are often seen. Rarely, mononuclear cellular infiltrates are seen near necrotic muscle fibers. On electron microscopy, focal myofibrillar degeneration and distortion of the Z-disks are common, but are not specific for LGMD.

Genetic testing:

This may define the specific type of LGMD, although genetic testing is problem- atic for several reasons. These include the heterogeneity of the disorder, many potential causes of the syndrome have not been fully elucidated, and even when the gene abnormality is known genetic testing may currently not be available.

– FSHMD – DM1 or DM2 – DMD or BMD

– Congenital myopathies

No specific therapy is known for LGMD at this time. Future therapies will have to target the specific molecular defect.

– Treatment of contractures, cardiac, and pulmonary disease follows the outlines for DMD

Diagnosis

Differential diagnosis

Therapy

– Genetic counseling is complex in LGMD due to the heterogeneity of the disease. It can be difficult to convince family members that the risk of having a severely affected child may be equally as high in those subjects with mild or severe disease.

LGMD is a progressive disorder, although the rate of progression depends on the type. Autosomal recessive LGMD usually progresses rapidly,with inability to walk in late childhood and death in early adulthood. In contrast, autosomal dominant LGMD even of childhood onset is usually only very slowly progres- sive. Respiratory involvement may occur later in the disease depending on the specific type of LGMD. This may result in pneumonia and early death. Myocar- dial changes may also occur in LGMD, depending on the type, although they are usually less severe than in the dystrophinopathies. Affected patients may develop a cardiac arrhythmia or sometimes congestive cardiac failure.

Galbiati F, Razani B, Lisanti MP (2001) Caveolae and caveolin-3 in muscular dystrophy.

Trends Mol Med 7: 435–441

Hack AA, Groh ME, McNally EM (2000) Sarcoglycans in muscular dystrophy. Microsc Res Tech 48: 167–180

Huang Y, Wang KK (2001) The calpain family and human disease. Trends Mol Med 355–

362

Moir RD, Spann TP (2001) The structure and function of nuclear lamins: implications for disease. Cell Mol Life Sci 58: 1748–1757

Moreira ES, Wiltshire TJ, Faulkner G, et al (2000) Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 24: 163–166

Tsao CY, Mendell JR (1999) The childhood muscular dystrophies: making order out of chaos. Semin Neurol 19: 9–23

Prognosis

References